JP2805873B2 - Hollow fiber type plasma separation membrane - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a medical hollow fiber type plasma separation membrane used for separating plasma components from blood,
More specifically, a hollow fiber type having excellent biocompatibility, no hemolysis, and improved hemolysis resistance, which is used in medical fields such as plasma exchange therapy and blood sampling of components from healthy persons. The present invention relates to a plasma separation membrane.

(Prior art field) Plasma separation, which separates blood plasma components from blood except blood cell components, is aimed at treatment such as plasma exchange therapy, which aims to remove etiological substances and toxic substances in plasma. It has been developed as a medical tool. However, in order to compensate for the absolute shortage of the supply of plasma raw materials in Japan against the increase in the use of plasma products due to recent advances in medical technology, blood donation by plasma separation has been institutionalized. The subject of the plasma separation method has been extended to healthy subjects. The plasma separation membrane used for such component blood donation is used for healthy persons, and requires a higher level of safety and biocompatibility than conventional plasma separation membranes for treatment. Cellulose acetate, polyethylene, polypropylene, polyvinyl chloride, polycarbonate, etc. are used as materials for plasma separation membranes, but these are sufficient for conventional plasma separation membranes in terms of biocompatibility and safety. Nothing was reached.
For example, in terms of biocompatibility, cellulosic membranes, which have been widely used as blood purification membranes in the past, are activated when the complement components in the blood come into contact with the membrane, causing the immune system to react. It has been known. Polyolefin-based membranes, which are said to be relatively excellent in biocompatibility, cannot be formed by the phase separation method, but are microporous and opened by the stretching method. When the blood cells are trapped in the pores, the parallel fibrillated polymer fibrils exert a strong stress locally on the erythrocyte curtain, causing hemolysis.

(Problem to be Solved by the Invention) The present invention provides a hollow fiber type plasma separation membrane having safety and biocompatibility which can be used for healthy donors (blood donors). Here, safety means that the membrane has a membrane strength that does not cause leaks and has no membrane defects such as pinholes, and that it does not generate hemolysis when it comes into contact with blood and performs plasma separation. By the way, biocompatibility generally refers to the reaction between the blood coagulation system and the immune system, but in plasma separation, the reaction of the coagulation system is blocked by an anticoagulant, and thus mainly refers to the reaction of the immune system. Shall be. An object of the present invention is to provide a hollow fiber type plasma separation membrane having improved safety, particularly improved hemolysis resistance and excellent biocompatibility, which is not available in conventional plasma separation membranes.

(Means for Solving the Problems) As a result of earnest research for solving the problems, the present invention has been reached. That is, a semi-cylindrical convex portion is formed on the inner surface of the hollow fiber type separation membrane that comes into contact with blood, and the distance (L) between the convex portions is expressed by the formula 1, and the height (H) is expressed by the formula 2. It is a hollow fiber type plasma separation membrane having improved properties.

1 μm ≦ L ≦ 20 μm (1) 1 μm ≦ H ≦ 10 μm (2) The material of the separation membrane to which the present invention is applied is a cellulose-based material.
Cellulose acetate, polyvinyl chloride, polyvinyl alcohol, polyolefin, polycarbonate,
Although it is a polysulfone-based polymer, polycarbonate is desirable from the viewpoint of biocompatibility and the like.

The spacing (L) and the height (H) of the semi-cylindrical projections provided on the inner surface of the hollow fiber type plasma separation membrane according to the present invention are shown in FIG. The projections are preferably formed in parallel with the longitudinal direction of the hollow fiber, and the pores formed on the membrane surface preferably have a smooth circular or oval shape.

The hemolysis referred to in the present invention means that the cell membrane of red blood cells is destroyed, the cells are crushed, and the cytoplasm is released. Since the hemoglobin (Hb) in the cells is released, the concentration of Hb released into the blood Can determine the degree of hemolysis (usually 3 mg / dl or less). The mechanism by which hemolysis occurs in plasma separation by a membrane is that when blood is filtered through a hollow fiber membrane, the transmembrane pressure (T
MP), a flow perpendicular to the membrane surface is formed, and a so-called cross flow (cross flow) is generated between the flow and the flow in the axial direction of the hollow fiber. The blood cell component reaches the membrane surface by the flow of the filtrate (plasma) but cannot pass through the pores of the membrane, so it is trapped on the membrane surface or rolls on the surface by the flow in the direction of the hollow fiber axis. It then flows again in the axial direction. At this time, the captured red blood cells are subjected to the force drawn into the pores by the TMP and the shearing force due to the blood flow in the axial direction.If this force exceeds the breaking limit of the red blood cell membrane, the cell membrane of the red blood cells is destroyed and hemolysis is caused. Will occur.

In the mechanism of such hemolysis generation, the point of hemolysis generation is that red blood cells are captured on the membrane surface, the red blood cells captured on the membrane surface are drawn into the pores and the hollow fiber axial direction. The two points are that the erythrocyte cell membrane is destroyed by the shear force caused by the flow.

Therefore, it is necessary to consider the means for preventing hemolysis in two stages. One is to provide a membrane structure so that red blood cells are not trapped on the membrane surface, and the other is to disperse the force applied to the red blood cell membrane so that the cell membrane of the red blood cells trapped on the membrane surface is not destroyed. Methods to prevent hemolysis are possible. The inventors of the present invention diligently studied such a point, and as a result, by forming the membrane as described above, the hollow fiber having improved hemolysis resistance exhibiting an effective effect on these two points. It has been found that it can be used as a type-type plasma separation membrane. That is, in order to suppress the capture of red blood cells on the membrane surface, by forming a semicylindrical projection parallel to the longitudinal direction of the hollow fiber on the membrane surface, the area where the red blood cells contact the membrane is reduced, The flow in the long axis direction in the hollow fiber is rectified, flow stagnation near the membrane surface is reduced, and red blood cells are less likely to be captured on the membrane surface. At this time, the interval between the vertices of the semi-cylindrical convex portion is made smaller than three times the maximum diameter of red blood cells (about 8.5 μm) to reduce the probability of entering the valley. Therefore, the interval (L) between vertices is 1 (μ
m) ≦ L ≦ 20 (μm), and the height of the apex is 1 (μm) ≦ H ≦ 10 (μm) in order to have a flow rectification effect in the longitudinal direction of the hollow fiber. It is necessary to be. Also, to prevent hemolysis of red blood cells trapped in the pores on the membrane surface, the pores are smooth circular or smooth oval formed by the phase separation method, and red blood cell membranes such as fibril or linear blinds. It is necessary not to have a structure in which stress concentration occurs locally.

The means for spinning a hollow fiber type plasma separation membrane having such a structure is to use a spinning stock solution with a high coagulation speed, raise the coagulation value of the inner solution, and stretch the inner surface quickly while slowly coagulating the outer surface. It is achieved by doing.

That is, by the difference in shrinkage in the diameter direction of the hollow fiber between the inner surface where solidification has already progressed by drawing and the outer surface where solidification is slower (small inner shrinkage and larger outer shrinkage), a semicylindrical convex portion is formed on the inner surface. What is important at this time is to lower the coagulation bath to lower the draft ratio at the time of spinning film formation to increase the diametrical shrinkage force of the hollow fiber, and to lower the coagulation value to slow the coagulation from the outside. It is desirable to use a coagulation bath with a high solvent concentration.

When polycarbonate is used as the hollow fiber membrane material, the concentration of the polycarbonate is 15 to 25%, and when it is 25% or more, no convex portion is formed on the inner surface. It is important that the internal solution and the coagulation bath have different coagulation rates such that the coagulation rate is fast inside and slow outside.For example, when using water as a coagulant, increase the amount of water in the inner solution and increase the amount of water in the outer solution. Control with less.

The temperature of the coagulation bath is usually at least 30 ° C.
Perform at a low temperature of ~ 20 ° C.

(Example) Production method of hollow fiber type separation membrane and evaluation measurement method The hollow fiber type plasma separation membrane is obtained by dissolving a polymer in a mixed solvent of a solvent and a non-solvent. After being discharged from a double tube nozzle together with the core liquid and allowed to travel in the air, it was produced by dry-wet spinning in which the liquid was introduced into a coagulation bath composed of the same components as the core liquid to form a solidified film. After washing the hollow fiber membrane with water, it was subjected to a hot water treatment at 121 ° C. in an autoclave, further immersed in a 50% glycerin aqueous solution, and dried to obtain a hollow fiber type plasma separation membrane. The hollow fiber inside diameter is
The thickness was 280 μm and the film thickness was 40 μm. In the method for evaluating the performance of the plasma separation membrane, a module is formed by an ordinary urethane resin bonding method to form a plasma separation module having a length of 20 cm and an effective membrane area of 0.2 m ² . Using ACD solution濾内bovine blood as an anticoagulant, while supplying bovine blood 50 ml / min, the plasma separation performance was evaluated, the method, for example artificial organ, 14, P.1
902-1910, (1985), a general evaluation method taught in the report of JRCS, Jiang Banno, Hiroyuki Ikeda et al.

The evaluation items were the maximum plasma separation speed QFmax and the sieving coefficient of plasma protein SC Total Protein. SC Tot
al Protein is defined by the following formula.

The hemolysis resistance was evaluated by the transmembrane pressure difference (TMP) at which hemolysis occurs. That is, TMP was determined in which the difference between the free hemoglobin concentration in the collected plasma and the free hemoglobin concentration in the blood supplied to the plasma separator measured by a colorimetric method using O-toluidine was 3 mg / dl or more.

Example 1 Polycarbonate resin (Mitsubishi Kasei NOVAREX) 20
Parts by weight, N-methylpyrrolidone (NMP)
Using a dope obtained by mixing and dissolving with 8 parts by weight of γ-butyrolactone, a weight ratio of water / NMP / γ-butyrolactone was obtained from a double pipe nozzle having an outer diameter of 1 mm, an annular slit having a width of 95 μm, and an inner liquid supply hole. Is discharged together with an inner solution having a composition of 35 / 58.5 / 6.5, and after traveling in the air for 2 cm, the same component as the inner solution is run in a coagulation bath having a composition of 30/63/7 to form a nozzle draft 17. Thereafter, the membrane was washed with water to obtain a hollow fiber membrane having a convex portion on the inner surface of the membrane. After performing the above treatment on this film,
It was modularized and evaluated.

Comparative Example 1 A dope obtained by mixing and dissolving 30 parts by weight of a polycarbonate resin (NOVAREX), 63 parts by weight of N-methylpyrrolidone and 7 parts by weight of γ-butyrolactone as a solvent was used.
A hollow fiber membrane was prepared in the same manner as in Example 1, but no convex portion was formed on the inner surface. This film was subjected to the same processing as in Example 1, and was evaluated after modularization.

In the plasma separation membrane of the present invention, no hemolysis was observed even at TMP of 300 mmHg. On the other hand, in the comparative example in which no convex portion was formed on the inner surface of the hollow fiber membrane, hemolysis was observed at TMP of 200 mmHg or less.

(Effect of the Invention) According to the present invention, a plasma separation membrane having excellent plasma separation performance and excellent hemolysis resistance can be provided.

[Brief description of the drawings]

FIG. 1 is a diagram showing a semi-cylindrical convex portion present on the inner surface of the hollow fiber membrane, and FIG. 2 is a diagram showing the height (H) of the convex portions and the interval (L) between the convex portions. .

Claims (1)

(57) [Claims] 1. A hollow fiber type plasma separation membrane, wherein a semicylindrical convex portion is formed on the inner surface of the separation membrane which comes into contact with blood, and the interval (L) between the convex portions is expressed by the following formula: A hollow fiber type plasma separation membrane having improved hemolysis resistance having a convex portion on the inner surface of the hollow fiber membrane, wherein the (H) is represented by the formula (2). 1 μm ≦ L ≦ 20 μm (1) 1 μm ≦ H ≦ 10 μm (2)